There are a large number of pat hological processes known, in the case of which extremely reactive free radicals are accumulated. The formation of these free radicals leads to the oxidation of unsaturated fatty acids (lipid peroxidation), which are important components of the cell membranes. This is a less specific, cell-destroying process altering or damaging the biomolecules. In this process functions of various levels of cells, organs or the whole organism may suffer injuries.
Due to their lipid peroxidation-inhibiting effect, antioxidant compounds assure protection against injuries induced by free radicals.
Active agents of compositions belonging to this structural and pharmacological group are believed to be incorporated to the membrane of neurons or glian cells and thereto counter balance pathomechanisms connected with lipid peroxidation which is a consequence of formation of reactive free oxygen radicals. The formation of such radicals is considered to play a decisive role in pathologic processes induced by injuries, accompanied by cell death. Since the role of the mechanisms mentioned is widespread and can be considered to the general in nearly all sectors of molecular pathology or pathobiology, respectively, it is obvious that any potential therapeutic utility of lipid peroxidation-inhibiting compounds should be in connection with an especially extended and diversified spectrum of syndromes, pathological pictures and disease groups.
Thus, compounds inhibiting the lipid peroxidation may have a therapeutical benefit not only in acute injuries (such as brain concussion, brain contusion, cerebral maceration, brain compression) or in acute shock of the brain circulation (arterial or venous thromboses, brain embolism, subarachnoidal haemorhages) but also in a number of other pathologic alterations or conditions affecting the central nervous system or other organ systems. The potential area of indication may involve such neuropsychiatric pathologic pictures as the Alzheimer's disease and Alzheimer-type dementiae, alcoholic dementia and central nervous system injuries accompanying the alcoholism, some so-called "negative" symptoms of schizophrenia, Parkinson's disease and Parkinson syndrome, amyotrophic lateral sclerosis, sclerosis multiplex, cluster headache as well as complications accompanying the neoplastic alterations of the brain.
Potential indications of using lipid peroxidation-inhibiting compounds in pathologic pictures of non-central nervous system origin may be e.g. forms of various severity of irradiation damages, septic or endotoxic shock, haemorrhagic shock, traumatic shock, stress-ulcus occurring as a consequence of major laesions, burn shock, conditions following extended surgical interventions, conditions following cardiopulmonar reanimation, reperfusion following organ transplantation, prevention of retrolental fibroplasia connected with the oxygen therapy of immature newburns, protection from the adriamycin cardiotoxicity, prevention of the reperfusion injury occurring as a complication of acute myocardial infarction (e.g. after thrombolytic treatment), some allergic reactions, insect bites, inflammatory processes of the skin (e.g. psoriasis, eczema), nephrosis syndrome (of immunological origin), rheumatoid arthritis, systematic lupus erythematosus, endogenic uveitis, bronchial asthma, emphysema as well as atherosclerosis of the blood vessels.
The importance of such compounds inhibiting lipid peroxidation is proven also by the high number of the most recent literature references (patent applications as well as scientific publications).
In the published PCT patent application No. WO 87/01706 the preparation of mainly aminosteroids is described, wherein an "amino group" is bound to the terminal carbon atom of the C-17 side chain. Double bond(s) in position 4 or positions 1,4 of ring A of the steroid skeleton, oxo- or hydroxyl group in position 3, .alpha.- or .beta.-alkyl group or halogen in position 6 and chiefly .alpha.-hydroxyl group in position 11 as well as .alpha.- or .beta.-methyl group in position 16 and a double bond in position 9(11) are present. The ring of the steroid skeleton may be saturated or aromatic. Some 21-aminosteroids are also described in which the double bond is present in position 17(20). In the case of compounds disclosed in this publication the disubstituted pyrimidine, triazine or pyridine ring is bound in the most cases through a piperazinyl group to the position 21. Among the compounds published 16.alpha.-methyl-21-{4-[2,4-bis(pyrrolidino)-6-pyrimidinyl]-1-piperazinyl} pregna-1,4,9(11)-triene 3,20-dione methanesulfonate (generic name: tirilazad mesylate) is in the second stage of clinical trials at present.
Similarly, the synthesis of steroid lipid peroxidation-inhibiting compounds is described in the published PCT application No. WO 87/07895. The synthesis of "amino esters" and "corticoid amino esters", above all "17-amino esters". "11,17-bis(amino) esters", "3,17-bis(amino) esters", "11-amino esters" and "3-amino esters", all of androstane structure, is discussed. According to this publication these compounds may be useful as inhibitors of lipid peroxidation occurring as consequences of spinal, cephalic and other injuries. The amino substituents have a structure similar to those mentioned in the preceding publication.
The preparation of novel "amino-9,10-secosteroids" is described in the published PCT patent application No. WO 88/07527. The amino substituent is bound to the terminal carbon atom of the C-17 side chain of the secosteroid. The amino substituents are similar to those described in the preceding publications.
The synthesis of lipid peroxidation-inhibiting compounds is described in the published European patent applications Nos. 0,389,368, 0,389,369 and 0,389,370, too.
The preparation of corticoid-type "21-aminosteroids" is described in the published European patent application No. 0,389,368. For example, a 4-[2,5-bis(diethylamino)-6-pyridinyl]-piperazinyl group may be bound to the C-21 carbon atom. The ring A of the sterane skeleton contains one or two double bond(s) whereas substituents characteristic of the corticoids may be present in positions 6, 9, 11, 16 and 17. A double bond may be present in position 9(11), too.
The synthesis of "amine derivatives" of 3-oxo-19-norsteroids is described in the published European patent application No. 0,389,370. As specific compounds 17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl) -17.alpha.-{3-[4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]-1-pro pynyl}estra-4,9 -diene-3-one, 17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-{3-[4-[5,6-bis (diethylamino)-2-pyridyl]-1-piperazinyl]-1-propynyl}estra-4,9-diene-3-one, 17.beta.-hydroxy-11.beta.-(4-di-methylaminophenyl)-17.alpha.-{3-[4-[2,6-bi s(diethylamino)-2-pyridyl]-1-piperazinyl]-1-propynyl}estra-4,9-diene-3-one, 17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-{3-[4-[2,6-bis (1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-1-propynyl}estra-4,9-diene-3 -one and 17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-{3-[4-[2,6-bis (pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]-1-propynyl}estra-4,9-diene-3-on e are exemplified.
The synthesis of aminosteroid derivatives with androstane skeleton, similarly showing a lipid peroxidation-inhibiting affect, are described in the published European patent application 0,389,369; these compounds similarly possess a lipid peroxidation-inhibiting effect. Examples of such compounds are e.g. 11.beta.,17.beta.-dihydroxy-17.alpha.-{3-[4-[2,6-bis (pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]-1-propynyl}-androsta-4,6-diene -3-one, 11.beta., 17.beta.-dihydroxy-6-methyl-17.alpha.-{3-[4-[2,6-bis(pyrrolidino)-4-pyrimi dinyl]-1-piperazinyl]-1-propynyl}androsta-1,4,6-triene-3-one, 11.beta., 17.beta.-dihydroxy-6-methyl-17.alpha.-{3-[4-[5,6-bis(dimethylamino)-2-pyri dyl]-1-piperazinyl]-1-propynyl}androsta-1,4,6-triene-3-one and 11.beta., 17.beta.-dihydroxy-6-methyl-17.alpha.-{3-[4-[3,6-bis(diethylamino)-4-pyrid yl]-1-piperazinyl]-1-propynyl}androsta-1,4,6-triene-3-one.
In the published European patent application No. 0,156,643 primarily the synthesis of water-soluble corticosteroid derivatives is described which are mainly characterized thereby that the hydroxyl group or an ester derivative thereof in position 11 is in the .alpha.-configuration or a double bond is present in position 9(11). Among the compounds described 17.alpha.-hydroxy-11.alpha.-(2,2-dimethylpropylcarbonyloxy)-pregna-1,4-die ne-3,20-dione-21-yl succinate sodium salt is considered to be the most effective lipid peroxidation-inhibiting agent.
In the published PCT patent application No. WO 91/11453 bis("amino")pyrimidinyl-piperazinyl derivatives containing an oxygen function in position 5 are disclosed, wherein a steroid molecule, 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ylmethyl group or a derivative thereof may be connected to the nitrogen in position 1 of the piperazine moiety. In this description 5-hydroxypyrimidine derivatives substituted by an alkyl group are also described.
Logically, the preparation of lipid peroxidation-inhibiting compounds was extended to the investigation of amine derivatives containing a non-steroid skeleton. Thus, e.g. in the published PCT patent application No. WO 88/08424 the preparation of novel aromatic and aliphatic bicyclic amine, cycloalkylamine, quinone-amine, amino ether and bicyclic amino ether derivatives are described which may be useful e.g. for healing cephalic and spinal injuries. From the derivatives described 2-{[4-2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]methyl}-3,4-dih ydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol dihydrochloride was investigated in detail.